205662353 2402-unit-4-exam-study-guide

Lymphatic Systems Course: BIOL 2402

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Blood Functions and Characteristics – is the only connective tissue in the body that is a fluid and its primary function is the transport of CO2-laden blood from the tissues to the lungs, where it is exchanged for O2, and the O2-rich blood is returned to the tissues. Under normal conditions, it is self-contained within the circulatory system – and the only time that changes is if there is damage to a vessel and the circulatory system is no longer a closed system. In appearance, blood is slightly viscous and somewhat tacky in consistency. While blood may appear to be a fluid, it is more correctly a suspension – since the formed elements are not so much dissolved in the plasma as much as they are suspended. In terms of color, blood is medium red – and becomes brighter or darker with the amount of O2 bound to the hemoglobin (if the blood is O2-depleted, it will appear a deep, ruddy, red, while O2-rich blood will be a bright scarlet red). In terms of taste, blood is slightly salty – due to the assorted salts dissolved in the plasma, and has a slight metallic taste due to the organometallic nature of hemoglobin. Because blood is a suspension, rather than a liquid, it is denser than water (because of the formed elements). Chemically,

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it is slightly alkaline – normal blood pH is 7.35 – 7.45 – and it’s temperature is approximately 38°C (even though normal body temperature is 37°C, normal blood temperature is always slightly higher – body temperature being a function of blood temperature heating the surrounding tissue, and there being a slight loss of temperature in radiant transfer). By composition, blood has three principal fractions – 1) formed elements 2) plasma, and 3) serum. By volume, formed elements account for 45% of whole blood, while plasma accounts for 55%, and serum is practically the same (55% – serum is plasma without any clotting factors). Blood’s average volume is 5-6 L (♂), and 4-5 L (♀).

1) Formed Elements (type of cell, name, and % by volume) – are the cellular components found in whole blood, and include erythrocytes (RBC’s), leukocytes (WBC’s), and platelets.

I. Erythrocytes (RBC’s – red blood cells) 4,7000,000 – 6,100,000 (♂), 4,200,000 – 5,400,000 (♀) per μl 45% of whole blood 6-8 μm diameter Anucleated Last 100- 120 days Primary function is transport and exchange of O2 and CO2

II. Leukocytes (WBC’s) 4,000 – 11,000 per μl <1% of whole blood

a. Granulocytes – cytoplasmic granules contain cytokines and other compoundsi. Neutrophils

2,500 – 7,500 per μl 54% - 62% of leukocytes 10-12 μm diameter Segmented nucleus Fine cytoplasmic granules – stains with both acidic and basic dyes (H&E) Lasts 6 hours to a few days Phagocytic action against bacteria and fungi

ii. Eosinophils 40 – 650 per μl 1% - 6% of leukocytes 10-12 μm diameter Bi-lobed nucleus Large cytoplasmic granules – stains with acidic dyes (Wright’s) Last 8 – 12 days Active against viral infections, allergy reactions, and parasites

iii. Basophils 10 – 50 per μl 0.25% - 0.45% of leukocytes 12-15 μm diameter Multi-lobed nucleus (generally 2, sometimes 3 lobes) Large course granules – stains strongly with basic/cationic dyes Granules contain histamine and heparin Active in inflammatory/histamine/allergy reactions, parasitic infections Lasts a few hours to a few days

b. Agranulocytes – cytoplasm does not contain granules

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i. Lymphocytes 1,000 – 3,600 per μl 25% - 33% of total leukocytes 7-8 μm diameter (average) – better classified as 5-8 μm (small), 10-12 μm

(medium), and 14-17 μm (large) Large, central nucleus Nucleus stains dark and evenly, but not consistently (eccentric staining) Very little cytoplasm around periphery 3 cell lines

o B cells – antibody-mediated immune responseo T cells – cell-mediated immune response

CD4+ cells – activate and regulate T and B cells CD8+ cells – attacks virus-infected/oncogenic cells Regulatory T cells – modulates immune response, prevents

autoimmune responses γδ T cells – similar to NK cells, able to initiate an immune

response directly against an antigen or against an MHC-antigen complex

o NK cells – T cells able to initiate an immune response directly against an antigen – does not need need to bind with MHC-antigen complex; attacks virus-infected/oncogenic cells

Lasts several hours to several years (or longer)ii. Monocytes

80 – 1,100 per μl 2% - 10% of total leukocytes 14-24 μm diameter Indistinct, segmented nucleus (‘U’-shaped) Cytoplasm stains weakly with basic dyes Nucleus shows stronger staining with basic dyes Capable of migrating from blood stream into tissues, and differentiating

into macrophages Active in inflammatory reactions, viruses, parasites, and chronic infections Suspected causal link between monocytes and atherosclerosis Lasts several hours to several days

III. Thrombocytes (Platelets) 200,000 – 500,000 per μl <1% of whole blood 2 – 4 μm diameter Anucleated Last 5 – 10 days Involved with clotting mechanism

2) Hematocrit (definition and average values, by sex) – per unit volume, is the ratio of erythrocytes to total volume. Its clinical significance is that it’s a measure of blood’s O2-carrying capacity. In terms of its clinical interpretation, a higher hematocrit indicates that erythrocytes can carry a heavier O2 load.

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This may be indicative of athletic training and a higher RBC count, possible blood doping with eyrthropoietin, or a short stay at a higher elevation (a short stay at higher elevations will stimulate an increase in erythropoiesis, resulting in a higher RBC count and a slightly elevated hematocrit – which returns to normal levels on return to lower altitudes; by contrast, a permanent move to a higher elevation will show an elevated RBC count and hematocrit for the short-term, but settle at, or near, normal levels shortly after the body adjusts to the higher elevation). In contrast, a below-normal hematocrit can alert surgeons to internal bleeding following surgery, help physicians diagnose iron-deficient erythropoiesis or chronic renal disease. Clinically normal hematocrit values are: 47% ± 5% (♂), and 42% ± 5% (♀).

3) Plasma Contents (composition, by volume) – plasma is predominately water, but it also contains a variety of proteins, as well as a number of electrolytes, nutrients, gases, vitamins, and regulatory substances in solution, as well as metabolic waste products.

Whole blood plasma fraction, by volume = 55%o Proteins – 7%

Albumin – 54% Globulin proteins (α, β, γ) – 38% Fibrinogen – 7% Other proteins – 1%

o Water – 91.5%o Solutes – 1.5%

Electrolytes Na+

K+

Ca++

Mg++

Cl-

HCO3-

Nutrients Glucose Fatty acid chains Amino acids

Gases O2

CO2

N2

Regulatory substances Enzymes Hormones

Vitamins Metabolic waste products

Urea Uric acid Creatinine

4) Gamma Globulins – are one class of proteins found within the plasma fraction of whole blood. By their name, they have a quaternary, globular structure (as opposed to a simple secondary structure as

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either an α-helix or a β-pleated sheet). Generically, gamma globulins are best represented by the basic structure found in immunoglobulins – but not all immunoglobulins are gamma globulins, and not all gamma globulins are immunoglobulins. Analytically, gamma globulins are best separated using gel electrophoresis – which separates proteins based on their molecular weight and net charge. As an electrical charge is applied to the gel, those proteins that are smallest in terms of structure and weight or have the strongest charge move the furthest down the gel. The result is a gel with several bands in each lane – each band represents a protein, and its position in the lane corresponds to its molecular weight and charge. Gel electrophoresis is best used for identifying raw protein fractions prior to purification.

5) Hemopoiesis – is the process by which all hematopoietic cells are produced. The multipotent stem cell, a hemocytoblast, goes through several mitotic divisions – forming additional hemocytoblasts and common myeloid and common lymphoid progenitor cells. With the formation of the common myeloid and common lymphoid oligopotent stem cells, hemopoiesis is set to begin the production of all the formed elements found in whole blood.

The common myeloid progenitor cell goes through four mitotic cycles – forming a megakaryo-blast, a proerythroblast, a mast cell, and a myeloblast. These cells are responsible for 1) thrombopoiesis 2) erythropoiesis 3) granulopoiesis, and 4) monocytopoiesis. Mast cells are a primitive cell line which still exists unchanged. In thrombopoiesis, stimulated by thrombopoietin – megakaryoblasts develop into promegakaryocytes and then megakaryocytes, the megakaryocyte ruptures, producing small, cellular fragments that are known as platelets. In erythropoiesis, stimulated by erythropoietin – the proerythroblast (a pronormoblast) develops into a basophilic erythroblast, then a polychromatic erythroblast, then an orthochromatic erythroblast (a normoblast), then a polychromatic erythrocyte (a reticulocyte), and finally an erythrocyte. In granulopoiesis, the neutrophils, eosinophils, and basophils are produced. The myeloblast goes through three mitotic divisions, producing a neutrophilic, eosinophilic, and basophilic promyelocyte. From each of these are produced neutrophilic, eosinophilic, and basophilic myelocytes. These develop into neutrophilic, eosinophilic, and basophilic metamyelocytes, which develop into neutrophilic, eosinophilic, and basophilic band cells, and these band cells differentiate into neutrophils, eosinophils, and basophils. In monocytopoiesis, a myeloblast develops into a monoblast, which develops into a promonocyte and then a monocyte. The monocyte then divides, forming a macrophage and a myeloid dendritic cell.

The common lymphoid progenitor, while not as diverse as the common myeloid progenitor, is just as important. The common lymphoid progenitor splits, forming a lymphoblast and a lymphoid dendritic cell. The lymphoblast is the stem cell for lymphopoiesis, and develops into a prolymphocyte, and then splits into a small lymphocyte and an NK cell. The small lymphocyte splits into a T cell and a B cell – and the B cell then develops into a plasma cell

6) Hemoglobin – is the central globular protein at the center of erythrocytes and plays an integral role in gas exchange and transporting O2 and CO2 from the lungs and throughout the body. Structurally, hemoglobin is composed of 4 globin chains (2 α and 2 β), and each globin chain has an Fe atom at its center. Because of its complementary structure, one O2 (or CO2) can bind to each Fe atom. On average, there are 250 million hemoglobin molecules in each erythrocyte, multiplied by 4 O2 molecules each, allows for 1 billion O2 molecules per erythrocyte. O2 is primarily transported by hemoglobin in the form of oxyhemoglobin (nearly 98%) and the remaining 2% is transported as elemental O2 in the plasma. Just as O2 is transported by hemoglobin as oxyhemoglobin, CO2 is transported by hemoglobin in one of three forms – the most prominent is as HCO3

- (70%), followed by carbaminohemoglobin (20%), and the remainder (10%) is transported dissolved in the plasma.

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O2 unloading in the tissues is accomplished by the Bohr effect, which causes the Hb-O2 binding affinity to decrease as the PCO2 increases. This process is balanced by the Haldane effect, in the lungs – which causes the Hb-CO2 binding affinity to decrease as the PO2 increases

7) Granulocytes vs. Agranulocytes (functions) – collectively, granulocytes function to aid macrophages and phagocytes with the destruction of bacteria, and dead or damaged cells. Additionally, they assist with fighting bacterial, fungal, and parasitic infections, as well as mediate histamine and allergy reactions – allowing for increased blood flow in infected areas, allowing the blood to form clots and restrict bacteria from spreading to other parts of the body. As important a role as granulocytes play in fighting infections and helping macrophages, agranulocytes play a much more critical role. While granulocytes can bind foreign antigens and present them to T cells or B cells so the foreign cells can be destroyed by antibodies or NK cells, the body would be defenseless and susceptible to a wide range of infections and diseases if there were no agranulocytes. Agranulocytes provide both arms of the immune system, with the B cells moderating the antibody-mediated immune system and the T cells moderating the cell-mediated immune system. The B cells – either as B cells or plasma cells possess the ability to produce antibodies against foreign antigenic epitopes, while the T cells have the ability to release cytokines in response to detecting (or being presented with) a foreign antigenic epitope – and coordinating the actions of granulocytes, plasma cells, phagocytes, and macrophages. And without NK cells, the body would be susceptible to any infection not detected by granulocytes, T cells, or B cells.

8) Major Histocompatability Complex (MHC) – is a large group of proteins that are essential for presenting antigenic epitopes to macrophages, T cells, or B cells so that it can be destroyed. There are two classes – MHC Type I, and MHC Type II molecules. In both cases, as antigens are detected, they are bound to the MHC molecule, forming a complex, so that cells (whether they be granulocytes, CD4+, CD8+, B cells, or NK cells) can be alerted that there are foreign cells (bacteria, parasites, viral particles, metastatic cancer cells) needing to be attacked and destroyed. MHC Type 1 molecules are specific to CD8+ and NK cells, while MHC Type II molecules are specific to CD4+ cells. Without the MHC proteins, the body’s immune system would effectively be blind – and not be aware, or be able to know, that foreign, non-self (virus-infected cells or cancer cells), or damaged self cells have been detected and need to be destroyed.

9) Chemotaxis – a process by which damaged or infected cells release an assortment of chemical stimuli and molecules, serving as signals to leukocytes – allowing them to locate the damaged cell(s), the location of the inflammatory/histamine response, the virus-infected cells, or metastatic tumor cells. This process allows the antibodies, T cells, and macrophages to locate, attack, and phagocytose cells or particles the body has identified as non-self.

10) Basophils – are one of the formed elements found in whole blood. Specifically, they are one of three types of granulocytic leukocytes (the other two being neutrophils and eosinophils), and make up 0.01% to 0.3% of the total leukocytes (per μl). Histologically, they are 12-15 μm in diameter with a large multi-lobed nucleus (usually 2, occasionally 3, lobes), and large cytoplasmic granules. Histochemically, the cytoplasmic granules stain a deep blue with basic (like hematoxylin) or other cationic dyes. The cytoplasmic granules contain both histamine and heparin. Functionally, basophils play a major role in both the histamine response, as well as hypersensitivity reactions. In response to tissue inflammation, basophils are transported to the site of inflammation, and histamine is released – restoring localized

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blood flow to near-normal levels. Basophils possess surface receptors that bind IgE, which assist with mediating hypersensitivity reactions (whether stimulated by pollen/mold/fungus or by food allergens). Current research is indicating that basophils may also contribute to the secondary immune response managed by T cells.

11) Lymphocytes – are another of the formed elements in whole blood. Specifically, they are one of two agranulocytes (the other being monocytes), and make up 25% to 33% of the total leukocytes (per μl). Histologically, they are 7-8 μm in diameter with a large, central, nucleus and very little cytoplasm. Histochemically, the nucleus stains deep and regularly, but not consistently (some nuclei, when stained, do not stain the same color from one cell to the next – this is known as eccentric staining). Within the lymphocytic cell type, there are three distinct cell lines – B cells, T cells, and NK cells. Microscopically, it is not possible to differentiate B cells from T cells from NK cells. This kind of distinction can only be done using flow cytometry and immunofluorescently-labeled monoclonal antibodies that bind specifically to surface markers of different families of lymphocytes (whether they be B cells, T cells, or NK cells). Next to macrophages, lymphocytes are the longest-lived of the formed elements in whole blood – living for years, sometimes for the entire lifetime of the individual. While all three cell lines have the same basic function, each individual cell line has its own unique role.

B cells regulate the body’s antibody-mediated immune response (as opposed to the cell-mediated immune response, regulated by T cells). B cells develop in the bone marrow (immature B cells) and are then transported to the spleen (transitional B cells), where they will differentiate and mature, and the mature B cells will be released in the blood. On stimulation by an antigen, B cells are responsible for producing antibodies to that antigen. When the antigen presents itself, the B cell will differentiate into either a plasma B cell or a memory B cell. Plasma cells, now activated, will produce large amounts of antigen-specific antibody, while memory B cells will retain the coding for the antigenic epitope – maximizing the secondary immune response to the antigen without the delay of requiring B cells to be converted to plasma cells before antibody production can occur.

In contrast, T cells regulate the body’s cell-mediated immune response. While B cells develop in the bone marrow and differentiate and mature in the spleen prior to being released into the blood, T cells develop in the cortex of the thymus, and become immunocompetent in the outer layer of the thymus cortex. Once transported to the thymus, thymocytes (immature T cells) go through both positive, and negative, selection. During positive selection, only those thymocytes that are capable of identifying ‘self’ are kept, while the others are destroyed. Thymocytes that survived positive selection move deeper into the cortex and go through negative selection. Those thymocytes that identify, and bind, too strongly with ‘self’ are also destroyed (otherwise there would be too great a chance for autoimmune diseases to develop at a later date). Histologically, there is no means of differentiating between a T cell and a B cell. The only way to distinguish between the two is by the surface markers present (or absent) on the T cell. This classification of distinguishing one population of T cells from another first began as common designators (Total T, Helper T, Suppressor/Cytotoxic T), and these soon changed to a more standard system (Total T became T11, Helper T became T4, Suppressor/Cytotoxic T became T8), and by the early 1980’s (partly brought on by the discovery of the HTLV-III virus), from the discovery that how well (or poorly) a patient with a particular disease does is, in part, due to the patient’s T4 and T8 count – and their T4/T8 ratio. By the mid-1980’s, this standard system was quickly being replaced with the current system of assigning each surface marker a specific CD (for Cluster designation) identifier – as the field of immunology was developing newer, better, protocols for sequencing these surface markers – creating a standard catalog of each marker, the marker’s sequence, chemical structure, and uniform identifier (to remove any ambiguity, so that any two cells with the same CDxx surface marker(s) could be identified as the same type of cell – regardless of where they were found, or their actions weren’t

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quite the same). Currently, T4 is now CD4, T8 is CD8, T11 is CD3, B cells are CD19, and NK (Natural Killer) cells are CD16.

CD4 cells play the largest role in cell-mediated immunity, as they are instrumental in activating B cells to become plasma cells – producing antibodies against antigens or pathogens which stimulated the B cell. CD8 cells attack cells which have become infected by a bacteria/virus or become oncogenic. Like memory B cells, there are memory T cells, which play much the same role. Just as CD4 cells can be considered the ‘on’ switch for mounting an immune response; there are a group of T cells called regulatory T cells that are the ‘off’ switch – and inhibit the cell-mediated immune response. Regulatory T cells also play a crucial role in preventing autoimmune diseases, by inhibiting the continued immune response once it is no longer needed.

NK cells are very similar to CD4 cells in function, but they differ in the initial binding. Whereas CD4 cells bind to antigens on MHC Type II surface markers, NK cells do not require antigens to be bound to the MHC Type II-antigenic complex – they can bind to antigens directly.

Similar to NK cells is another group of T cells, called γδ T cells – which, like T cells, bind to MHC-antigen complexes, but, like NK cells, can also bind directly to the antigen. Currently, there is very little known about γδ T cells other than their similarity to T cells and NK cells. Any information about the sequencing or structure of the surface markers is still strong supposition, at best.

12) Thrombocytes – are the proper term for platelets. Thrombocytes develop from megakaryocytes – which are the mature form of megakaryoblasts, which develop from hemocytoblasts - the multipotent stem cell from which all hematopoietic cells (erythrocytes, reticulocytes, neutrophils, eosinophils, basophils, lymphocytes, monocytes, megakaryocytes, mast cells, and glial cells) arise. Hemocytoblasts give rise to five blast cells, each belonging to a specific cell line – 1) proerythroblast 2) myeloblast 3) lymphoblast 4) monoblast, and 5) megakaryoblast. Proerythroblasts develop into polychromatic erythroblasts, which mature into erythrocytes. Myeloblasts develop into progranulocytes, which mature and differentiate into granulocytes (neutrophils, eosinophils, and basophils). Lymphoblasts and monoblasts mature into Agranulocytes (lymphocytes and monocytes, respectively). Megakaryoblasts develop into megakaryocytes, which then begin going through repeated mitotic cycles without cytokinesis – resulting in singular, massive cells, with as much as 32 times the normal amount of genetic material. On stimulation by thrombopoietin, it’s believed that the cellular membrane of megakaryocytes form membranous processes all along the periphery of the cell, and it’s these processes that, when pinched off – forming cellular fragments – develop into thrombocytes. After megakaryocytes have degenerated – forming thrombocytes in the process (approximately 2-5000 thrombocytes per cell) – the remnant of the megakaryocyte makes its way to the lungs, where it’s broken down and digested by alveolar macrophages.

13) 3 Factors That Prevent Blood Loss – are responses the body takes to restrict blood flow to a damaged vessel, and initiate a localized cascade reaction to create a clot – sealing the vessel wall. The first step is initiating a vascular spasm in the vessel. The vascular spasm is the vasoconstriction of the vessel in response to the injury. Factors contributing to the vasoconstriction can, and do, include stimulation of the tunica media by sympathetic nerve fibers, chemotactic stimuli by platelets and endothelial cells, and proprioceptor stimuli. Paradoxically, the efficiency of the vascular spasm mechanism increases with the amount of tissue damage. As simple a step as this may seem, the body can minimize blood loss by maximizing vasoconstriction of the damaged vessel before moving on to the next step. The second step is the creation of a platelet plug attached to the edges of the damaged vessel, and then attached between the edges. Under normal circumstances, platelets will not adhere to the endothelium of blood vessels, but when a vessel wall is damaged, platelets adhere very strongly to the collagen fibers in the vessel

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wall. As platelets begin adhering to the damaged edges, a large glycoprotein (von Willebrand factor) in the blood stabilizes the bond between platelet and collagen – allowing for more and more platelets to bind with the collagen. As more platelets bind to the collagen, they release three compounds – ADP, serotonin, and thromboxane A2. ADP works to increase the adhesiveness of the platelets, while serotonin and thromboxane A2 both function to increase the vascular spasm as well as enhance the platelets adhesive properties. The combination of these three compounds form a synergistic positive feedback loop – the more platelets there are, the more compounds are released magnifying the effects of the compounds, causing more platelets to bind to the collagen. The third, and final, step is coagulating the platelets in the plug – sealing the damage to the vessel wall. As coagulation begins, fibrin filaments begin to form between the platelets – forming a mesh holding the platelets together. This is commonly the most visible of the three steps in repairing a wound, as the blood clots – leaving a meshwork of fibrin filaments. This is also the step in which the body launches the cascade reaction involved in blood clotting – a coordinated, and orchestrated reaction in which an array of 13 plasma proteins (synthesized by the liver) come together in a specific sequence with the end result being the formation of a very strong fibrin mesh which protects the vessel wall while it is repaired, and holds the platelet plug in place – to prevent any further damage to the vessel wall while it’s being repaired.

14) Agglutinogens – are protein surface markers found on erythrocytes, and used to assign a blood type based on which surface markers are, or are not, present. There are two agglutinogens – Type A and Type B – and their presence or absence determines Blood Types A, B, AB, and O.

15) Universal Blood Donor and Universal Blood Recipient – are the terms applied to two of the Landsteiner blood group designations. Specifically, because of their genotypes, individuals with one of these two phenotypes can either give blood to any other blood type (‘universal donor’) or receive blood from any other blood type (‘universal recipient’). The universal donor is type O- (genotype OO and the Rh factor is negative), and the universal recipient is type AB- (genotype AB and the Rh factor is negative). Because erythrocytes are typed by the agglutinogen present on their cell membrane, erythrocytes possessing a different agglutinogen will induce agglutination of the mixed cells. This is the underlying principle of blood typing and matching utilized by hospitals and blood banks across the globe. Blood type A possesses blood agglutinogen A, and will agglutinate if mixed with blood types B or AB. Similarly, blood type B possesses blood agglutinogen B, and will agglutinate if mixed with blood types A or AB (in both cases, because type AB blood possesses both A and B agglutinogens, agglutination will still occur, but not as strongly). Blood type O is not the presence of an agglutinogen, but rather the absence of an agglutinogen – and is the result of a homozygous recessive combination, OO. Type A or Type B blood is the result of either a homozygous AA/BB, or heterozygous AO/BO combination, respectively. Type AB blood will only occur as a co-dominant combination of AB. Because agglutination occurs when ‘non-self’ agglutinogens are present, Type O- blood may be given to anyone and agglutination will not occur, just as Type AB- blood can receive blood from anyone and agglutination will not occur. It is important to note that the Rh- is not an oversight, as overlooking the Rh compatibility – while not lethal – may induce mild to moderate anemia in the patient, as well as increase the patient’s susceptibility to infection by toxoplasmosis.

16) ABO Blood Types – is the system on which the entire science of typing blood is based. First discovered by Karl Landsteiner, in 1900 (and many other researchers produced similar research independently), it establishes the presence of surface proteins on erythrocytes as being the distinguishing factor between one blood type and another. Work was done which established blood types A, B, and O (hence the name ‘ABO’, while the fourth, AB, was discovered later), and later work established the

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structure of these surface markers, the heritability (establishing the genetic link between transference of the parental genotype to a child), as well as the location and sequencing of the genes which code for the surface markers. The basis for all three surface markers is the H antigen, coded by a gene sequence on chromosome 19. This H antigen is a carbohydrate sequence (fucose—galactose—acetylglucosamine—galactose) bound to a transmembrane protein. The A, B, and O markers are coded by a gene sequence on chromosome 9 which, when translated, adds another carbohydrate to the H antigen. For blood type A, acetylgalactosamine is added at position 2 (fucose—acetylgalactosamine, galactose—aceytlglucosamine—galactose). Blood type B codes for an additional galactose at position 2 (fucose—galactose, galactose—acetylglucosamine—galactose). Blood type O actually results from a nucleotide deletion (a guanine is deleted – causing a frameshift, resulting in an entirely different protein). Because of this frameshift, the protein translated for type O is enzymatically inactive – leaving the H antigen unchanged (fucose—galactose—acetylglucosamine—galactose). Blood type AB presents with both A and B surface markers in fairly equal proportions. A few years after birth, anti-A and anti-B antibodies (isoantibodies – antibodies produced by an individual against antigens produced by members of the same species) are produced, protecting against foreign or mismatched blood. Anti-A and anti-B antibodies are usually IgM (which are unable to cross the placental barrier), while individuals with type O produce anti-A and anti-B antibodies that are IgG. Even though type O and type AB are considered to be universal donors and recipients, respectively, it must be remembered that this only applies to packed erythrocytes – not whole blood, because anti-A and anti-B antibodies also exist in the serum. There is also a genetic link between blood type and an increased predisposition to bleeding, because the ABO antigen is also expressed on von Willebrand protein. Because of this, people with type O are at higher risk of uncontrolled bleeding due to lower levels of von Willebrand in their system. Just as type O is the result of an inactive protein – resulting in the H antigen being the surface marker, there is a mutation resulting in a very rare blood group (type hh) called the ‘Bombay Blood Group’. In these individuals, the gene for the H antigen is missing or defective, and as such their bodies are unable to produce the H antigen precursor. In these individuals, their erythrocytes do not have either A or B antigens (like type O – so they can effectively donate to types A, B, AB, and O), but because they do not have the H antigen either, their bodies do produce anti-H antibodies – so the only blood they can receive is type hh, otherwise their body will attack, and lyse, the non-hh blood. Type hh blood has a very low incidence – only as high as 0.0004% globally, and perhaps as high as 0.01% in some parts of India (Mumbai, among them).

17) Mediastinum – is that space, within the thorax, where the heart is located. Bounded superiorly by the thoracic inlet, inferiorly by the diaphragm, and by the lungs on either side, the remaining space - occupied by the heart, aorta, thymus, thoracic trachea, esophagus, associated lymph nodes, and neural pathways – is the mediastinum, which can be further subdivided into the superior mediastinum (extending from the superior thoracic inlet to the fusion of the manubrium and the body of the sternum (sternal angle, or angle of Louis), and the inferior mediastinum (extending from the angle of Louis to the diaphragm). The inferior mediastinum can be further divided into the anterior mediastinum (anterior to the pericardium), the middle mediastinum (containing the pericardium), and posterior mediastinum (posterior to the pericardium).

18) Cardiac Tissue (4 layers) – consists of 1) the pericardium 2) the epicardium 3) the myocardium, and 4) the endocardium. The outermost layer, the fibrous pericardium, has a high collagen content and serves to protect the heart as well as anchor it to anatomic structures within the mediastinum. Immediately underneath the fibrous pericardium is the serous pericardium – whose parietal layer is immediately beneath the fibrous pericardium. Beneath the parietal layer of the serous pericardium is the pericardial

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sac – filled with pericardial fluid, which serves to reduce the friction created by the serous pericardium sliding against itself and the heart sliding against the pericardium as it beats. The inner layer of the serous pericardium, the visceral pericardium, is actually contiguous with the epicardium of the heart. Beneath the epicardium is the myocardium – composed of cardiac myocytes interspersed with cardiac autorhythmic fibers. The innermost tissue layer is the endocardium – and just like any other hollow organ in the body, provides a smooth, low-friction surface allowing the internal surfaces of the heart to slide past each other as the chambers contract and relax.

19) Heart Blood Vessels (Coronary Arteries) – the coronary arteries arise from the base of the aortic trunk, forming a left, and a right coronary artery – running along the coronary sulcus (an anatomical landmark on the heart, separating the atria from their respective ventricles). The right coronary artery runs to the right margin of the heart, bifurcating, to form two major arteries – the right marginal artery running along the right anterolateral margin of the heart (perfusing the right lateral side of the heart), and the posterior interventricular artery running along the posterior interventricular sulcus (perfusing the apex of the heart and the posterior ventricular walls). The left coronary artery also creates two major branches from a bifurcation. Arising from the left coronary artery are the circumflex artery, running from the margin of the left coronary sulcus and continuing around to the posterior aspect of the heart (perfusing the left atrium and the posterior wall of the left ventricle), and the left anterior descending artery (anterior interventricular artery) running along the anterior interventricular sulcus (perfusing the interventricular septum and the anterior walls of both ventricles). As the posterior interventricular artery nears the apex of the heart, it ramifies – forming a small, diffuse capillary network with the left anterior descending artery. After perfusing the myocardium, the coronary arteries form capillary beds which develop into the venous return. Although there are several cardiac veins (just as there are coronary arteries), the three largest veins are the great cardiac vein (paralleling the circumflex artery), the middle cardiac vein (paralleling the posterior interventricular artery), and the small cardiac vein (paralleling the right marginal artery). These three large veins join together, forming the coronary sinus, which drains into the right atrium. There are other cardiac veins (posterior cardiac vein, anterior cardiac vein, and smaller veins and venules) that either anastomose with the coronary sinus or drain directly into the right atrium.

20) Conduction System of the Heart – is composed of 1) the sinoatrial node 2) the atrioventricular node3) the atrioventricular bundle (bundle of His) 4) the left and right bundle branches, and 5) the Purkinje fibers (running through the ventricular myocardium). The sinoatrial node is the ganglionic nerve bundle that is the pacemaker of the heart (because no other nerve bundle in the heart has a faster depolarization rate – for this reason, it's characteristic rhythm – the sinus rhythm – determines heart rate). Both thesinoatrial and atrioventricular bundles are innervated by the sympathetic and parasympathetic nervous systems as well as the vagus nerve. Despite this, only the sympathetic nervous system can moderate both the heart rate and the contractile force. The parasympathetic nervous system can only moderate the heart rate – since it does not innervate the cardiomyocytes in the atria and ventricles. Stimulating the nerve fibers of the vagus nerve that innervate the sinoatrial node has the effect of reducing the heart rate. If the nerve fibers of the vagus nerve that innervate the sinoatrial node were severed, the heart rate would actually increase ≈25 bpm (to ≈100 bpm) – this is known as vagal tone. As the sinoatrial node depolarizes, the action potential spreads – crossing the right atrium – arriving at the atrioventricular node. Once at the atrioventricular node, there is ≈0.1 s delay, allowing the atria to enter systole before the ventricular myocardium begins to depolarize and enter systole. As the atria complete systole, the action potential continues to propagate – arriving at the atrioventricular bundle (bundle of His). Once at the bundle of His, the action potential splits – following the separate (left and right bundles down to the

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apex of the heart. At the apex, the action potentials follow the bundle branch fibers along the ventricular walls, following the Purkinje fibers. Ventricular systole begins almost as soon as the action potentials start propagating along the Purkinje fibers. On average, the delay between the onset of depolarization at the sinoatrial node and the completion of ventricular systole is ≈220 ms.

21) Electrical Activity of Cardiac Muscle Contractions – the heart's autorhythmic cells control the heart's ability to beat. Unlike cardiomyocytes or striated muscle cells, autorhythmic cells do not maintain a stable resting potential. The cell membranes of these cells have an unstable resting potential, and continuously depolarize – always drifting close to the threshold necessary to generate an action potential. These pacemaker potentials – or prepotentials – initiate the action potentials that spread throughout the heart, triggering its characteristic rhythmic contractions. The pacemaker potential in these cells is possible because of the special properties of the ion gates in the cell membrane. In these cells, hyperpolarization at the end of an action potential triggers the closing of K+ gates and opening of Na+ gates. With the influx of Na+, the intramembrane potential becomes less negative – and as threshold approaches (-40 mV), Ca++ channels open. It is the sudden Ca++ influx (rather than the Na+ influx) that is responsible for the rapid depolarization and generation of the action potential. Following the sudden depolarization, autorhythmic cells repolarize just as fast, opening K+ gates and releasing K+ – repolarizing the cell, just to begin the rapid depolarization all over again.

22) EKG (ECG) – is a graphic recording of the heart’s electrical activity. A popular misconception is that an EKG is a visual representation of a single impulse generated by the heart. Actually, an EKG is a visual representation of all the impulses, in toto, generated by the heart and transmitted throughout the body. An EKG requires a minimum of 3 leads – to measure the voltage difference between 1) the left and right arm 2) the left leg and right arm, and 3) the left leg and left arm. The characteristic 3-peak tracing seen in an EKG is actually a combination of seven regions – and each region is significant in terms of what it tells the cardiologist.

P wave – lasts about 0.08 s; during normal atrial depolarization, the impulse is directed from the sinoatrial node towards the atrioventricular node, and spreads from the right atrium to the left atrium.

PR interval – lasts 0.12 s - 0.2 s; is measured from the beginning of the P wave to the beginning of the QRS complex. The PR interval reflects the time the impulse takes to travel from the sinoatrial node through the atrioventricular node and enter the ventricles. The PR interval is therefore a good estimate of atrioventricular node function.

PR segment – lasts 0.05 s - 0.12 s; the PR segment connects the P wave and the QRS complex. This coincides with the impulse conduction from the atrioventricular node to the bundle of His to the bundle branches and then to the Purkinje fibers. Because a contraction is not being produced, this shows as a flat line on the EKG. The PR interval's importance is in its clinical relevance.

QRS complex – lasts 0.08 s - 0.12 s; the QRS complex reflects the rapid depolarization of the right and left ventricles. Compared to the atria, the myocardium of the ventricles is much thicker, so the amplitude of the QRS complex is usually much larger than the P-wave.

J-point – only serves as a landmark. It is the point at which the QRS complex finishes and the ST segment begins. The J-point is used as a reference to measure the degree of ST elevation or depression (if present).

ST segment – lasts 0.08 s - 0.12 s; the ST segment connects the QRS complex and the T wave. This segment represents the period when the ventricles are depolarized.

T wave – lasts 0.16 s; the T wave represents the repolarization of the ventricles. The interval from the beginning of the QRS complex to the apex of the T wave is referred to as the absolute

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refractory period. The last half of the T wave is referred to as the relative refractory period (or vulnerable period).

ST interval – lasts 0.32 s; The ST interval is measured from the J-point to the end of the T wave. QT interval – lasts 0.3 s - 0.43 s; the QT interval is measured from the beginning of the QRS

complex to the end of the T wave. A prolonged QT interval is a primary risk factor for ventricular tachyarrhythmias and sudden death. The QT interval varies with heart rate - and for clinical relevance, this requires a correction:

Where: the value for QT is taken from the EKG, and RR is the interval from one R wave to the

next (and mathematically, RR = ), and QTC is the QT value, corrected for heart rate.

U wave – the U wave is not always seen, since it's typically a low amplitude impulse – by definition, it follows the T wave.

Although an EKG can be done with as few as 3 leads, it’s recommended that 10 to 12 leads are used. This allows the cardiologist to get the basic tracing, as well as record impulses from different angles – in case there are ischemic areas in the heart, or atherosclerotic plaques are developing in some of the coronary arteries (that might not be detected on auscultation, and an angiogram is considered unnecessary at the time).

23) Cardiac Cycle – includes all events associated with the blood flow through the heart during one complete heartbeat – from atrial systole and diastole, to ventricular systole and diastole. The physical events of the cardiac cycle always follow the electrical events seen in an EKG. The cardiac cycle is characterized by a succession of changes in the pressure and volume of blood in the heart. Because blood is circulating continuously, an arbitrary start point for the beginning of the cardiac cycle must be selected. By convention, the standard starting point for the cardiac cycle is with the heart completely at rest – with both atria and ventricles relaxed, and the heart is in mid-to-late diastole.

1. Ventricular filling (mid-to-late diastole) Intracardiac pressure is low Pulmonary and aortic semilunar valves are closed Venous return is filling the right atrium and flowing through the tricuspid valve,

filling the right ventricle The right ventricle almost full, the tricuspid valve begins closing (the remaining

blood will fill the right ventricle as the right atrium contracts) As the sinoatrial node depolarizes, the atria contract (P wave) – causing a slight

increase in intracardiac pressure – forcing the blood left in the atria into the ventricles

With the atria in systole, the ventricles are at maximum volume – holding as much blood as they can (end diastolic volume - EDV)

The atria enter atrial diastole, quickly followed by the ventricular myocardium beginning to depolarize (QRS complex)

The atria remain in diastole for the remainder of the cardiac cycle2. Ventricular systole

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As the ventricles enter systole, intraventricular pressure quickly increases – closing the atrioventricular valves

From the time the atrioventricular valves are closed and the ventricles are sealed chambers – and the blood volume is constant – is the start of the isovolumetric phase

As the intraventricular pressure continues to increase, and it exceeds the pressure in the pulmonary and aortic trunks – the pulmonary and aortic semilunar valves open, ending the isovolumetric phase

At this point – the ventricular ejection phase – the intravascular pressure in the aorta is ≈ 120 mm Hg

3. Isovolumetric relaxation (early diastole) The ventricles enter diastole as the ventricular myocardium begins to repolarize

(T wav) Blood remaining in the ventricles (end systolic volume – ESV) is no longer

compressed, and the intraventricular pressure decreases rapidly The sudden drop in intraventricular pressure creates a localized vacuum, drawing

blood in the pulmonary and aortic trunks back towards the ventricles – closing the pulmonary and aortic semilunar valves in the process

As the aortic semilunar valve closes, there's a sudden, slight increase in intravascular pressure resulting from the temporary backflow of blood against the cusps of the semilunar valve – and this can be heard on auscultation, and is known as the dicrotic notch

With an average heart rate of ≈75 bpm, the heart beats once every 0.8 s. Atrial systole lasts for 0.1 s and ventricular systole lasts for 0.3 s – the remaining 0.4 s is known as the quiescent period.

24) 0.8 Seconds – given a clinically average heart rate of 72 bpm, 0.8 seconds (800 ms) is the time it takes the heart to beat once.

25) Autorhythmic Fibers – account for approximately 1% of cardiac muscle fibers which, unlike striated and most cardiac muscle fibers, are capable of initiating not only their own spontaneous depolarization, but that of the rest of the heart, as well.

26) Starling’s Law of the Heart – allowing the walls of the ventricle to stretch further, and the ventricle to fill with more blood, will allow for a stronger ventricular contraction and a larger ejection volume. Unlike striated muscle fibers (which are kept at optimal length for developing maximum tension), cardiac fibers are actually kept at a shorter than normal length. By increasing the diastolic fraction – stretching the cardiac fibers in the process – the contractile force of the cardiac fibers is increased, which has the effect of increasing not only the strength of the ventricular contraction but also the ejection volume.

27) Positive Inotropic Factors – are a group of chemicals and compounds which have the effect of increasing the contractile force of the heart’s cardiomyocytes. Most positive inotropic factors currently in use belong to one of nine groups.

Berberine – even though it is a plant product with antifungal/antibacterial properties and has some efficacy against C. albicans and may be of use combating MRSA – in cardiology, it has the effect of enhancing the cAMP second messenger system, increasing Ca++ uptake, and prolonging ventricular diastole

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Bipyridine derivatives (Inamrinone, Milrinone) – are phosphodiesterase inhibitors, which increase the effects of the cAMP second messenger system, increase Ca++ uptake, and prolong ventricular diastole

Calcium – increases Ca++ levels, prolongs ventricular diastole Calcium sensitizers (Levosimendan) – acts as a Ca++ analog and binds to troponin-C, increasing

Ca++ sensitivity Cardiac glycosides (Digoxin) – prolongs the plateau phase of the cardiac cycle, slowing

ventricular contraction Catecholamines (Dopamine, Dobutamine, Dopexamine, Epinephrine/Norepinephrine,

Isoprenaline) – are sympathomimetic hormones secreted by the adrenal gland, and have the natural effect of increasing heart rate

Eicosanoids (Prostaglandins) – are natural vasoconstrictors, and have the added effect of controlling the movement of Ca++ into cardiomyocytes

Phosphodiesterase inhibitors (Enoximone, Milrinone, Theophylline) – as with Bipyridine derivatives, increase the effects of the cAMP second messenger system by blocking phosphodiesterase – prolonging ventricular diastole by increasing Ca++ levels

Glucagon – releases glucose, making it available to the cardiomyocytes, functioning as a synergistic agonist as glucagon levels are affected by sympathetic stimulation and catecholamines

28) Medulla Oblongata Cardiac Control Center – are the two centers in the medulla oblongata responsible for maintaining, and regulating, the heart rate – increasing or decreasing it as necessary. The cardioacceleratory center – located in the lateral nuclear group of the reticular formation of the medulla oblongata – is connected by preganglionic fibers in the T1-T5 region to ganglionic fibers in the cervical and upper thoracic sympathetic trunk. Postganglionic fibers run from the sympathetic trunk through the cardiac plexus and enter the heart – connecting with the sinoatrial and atrioventricular nodes, myocardium, and the coronary arteries. The cardioinhibitory center – located in the medial nuclear group of the reticular formation of the medulla oblongata – is connected to the parasympathetic dorsal motor nucleus of the vagus nerve by primary axons. From there, vagus nerve fibers send inhibitory impulses to the heart. Many of the parasympathetic nerve fibers are found in ganglia within the ventricular wall, with postganglionic fibers innervating the sinoatrial and atrioventricular nodes.

29) Receptors Control of Heart Rate – throughout the atrial and ventricular walls, as well as the trunks of the venae cavae and aorta, are high concentrations of both M2 muscarinic and β1-adrenergic receptors. These receptors, sensitive to acetylcholine and epinephrine, respectively, regulate heart rate in response to stimulation by the sympathetic and parasympathetic nervous systems. When the sympathetic nervous system is triggered, in response to physical or emotional stimuli, epinephrine is released and binds to the β1-adrenergic receptors – stimulating the sinoatrial and atrioventricular nodes to fire faster by increasing their impulse conduction speeds and increasing contractions – resulting in an increased ejection fraction. Sympathetic agonists include isoprenaline and dobutamine, while sympathetic antagonists include metoprolol and atenolol (both of which belong to the category of cardiac beta blockers). Counterpoint to the sympathetic nervous system is the parasympathetic nervous system, returning the heart rate to normal after the emotional or physical stimuli that triggered the sympathetic response has passed. The parasympathetic nerve fibers release acetylcholine, which binds to M2 muscarinic receptors – returning the heart rate to normal sinus rhythm by decreasing the depolarization speed and reducing the contractile strength of the atrial cardiomyocytes, decreasing the impulse conduction speed of the atrioventricular node, and decreasing the contractility of the ventricular myocardium.

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30) H + Effect on Heart Rate – elevated [H+] and acidosis will have an initial positive inotropic effect, but as the [H+] increases and blood pH drops below 7.2 it starts to rebound and have a negative inotropic effect. Increased contractility and heart rate is seen at pH>7.2, and contractility and heart rate begin to decrease as pH<7.1.

31) Vasa Vasorum – are found in the tunica externa of larger blood vessels. In the larger diameter vessels, both the tunica intima and tunica media receive adequate perfusion from the lumen, but the tunica externa is often too thick to be adequately perfused. To compensate, the body has developed a network of micro-capillaries which run throughout the tunica externa of the larger vessels – allowing much-needed O2 to reach cells otherwise unable to absorb O2 through simple diffusion alone.

32) Blood Vessel Tissue Layers – from the luminal space outwards, are the 1) tunica intima 2) tunica media, and 3) tunica externa. The tunica intima contains the endothelium (composed of simple squamous epithelium) facing the luminal space and in vessels larger than 1 mm in diameter, a subendothelial layer (a thin lamina propria) between the tunica intima and the tunica media. The tunica media is a loose triple layer composed of smooth muscle fibers sandwiched between thin elastin sheets. The thickness of the tunica media varies between arteries and veins (arteries need a thicker tunica media than veins, to maintain a constant hydrostatic pressure and keep blood flowing), as well as smaller versus larger vessels (the tunica media is thicker in the larger vessels for the same reason it’s thicker in arteries – the larger the vessel, the more constrictive force is needed to maintain the same pressure). Sympathetic nerve fibers are found throughout the tunica media, providing autonomic stimulation of the muscle fibers. Surrounding the tunica media is the tunica externa, a layer of loose collagen fibers which help to reinforce the vessel as well as anchor it to surrounding anatomic structures. The tunica externa is interlaced with nerve fibers, lymphatic capillaries – and in larger vessels, micro-capillaries of the vasa vasorum are also found in the tunica externa. Comparing arteries and veins – the lamina propria of the tunica intima is thicker in veins than in arteries, the elastin sheets found in the tunica media of arteries is absent in veins and the tunica media in veins is thinner, and an adaption found in veins that is absent in arteries are recurrent infoldings of the tunica intima – forming rudimentary valves – to prevent the backflow of blood within the vein.

33) Vasoconstriction vs. Vasodilation – are the terms applied to the reduction or increase in luminal diameter, respectively, of blood vessels. Vasoconstriction results from the release of epinephrine by sympathetic nerve fibers and binding to α1-adrenergic receptors in the tunica media; and vasodilation results from the release of acetylcholine by parasympathic nerve fibers and binding to M3 muscarinic receptors in the tunica intima – causing the endothelium to release nitric oxide, which diffuses into the smooth muscle of the tunica media – causing the smooth muscle fibers to relax, and the vessel to vasodilate.

34) Metarterioles – are arterioles arising from an arteriole and anastomosing directly with a venule, without first developing into a capillary network between the arteriole and venule. Capillaries are able to develop from metarterioles, forming collateral capillary networks between arterioles and venules.

35) 120/80 mm Hg – is the clinically normal blood pressure for a healthy adult, at rest. Blood pressure is one of the four, standard, vital signs (temperature, heart rate, respirations, and blood pressure) and is

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measured by a sphygmomanometer. A person’s blood pressure (BP) is the ratio of their

and measured in mm Hg. While sphygmomanometers no longer require a column of mercury to measure blood pressure (aside from the known hazards of heavy metal poisoning, and current models use electronic sensors), it’s important to understand the history to grasp the importance of what’s being measured. By definition, a mm of Hg is the pressure required to raise a column of mercury (nearly 14x as dense as water) by 1 mm. By extrapolation, a normal systolic pressure of 120 is the equivalent of raising a column of Hg almost 5” – or in simpler terms, is enough to lift nearly 50 pounds. A person’s systolic pressure is the maximum pressure exerted on the arterial wall – near the end of the cardiac cycle, when the ventricles are contracting. In contrast, a person’s diastolic pressure is the minimum pressure exerted on the arterial wall – near the beginning of the cardiac cycle, when the ventricles are filling with blood. A person’s BP is not constant, as it changes not only throughout the day, but it also varies between beats – in response to external factors (stress, diet, disease, exercise). Hypertension is the condition when the systolic pressure is significantly higher than 120, while hypotension is the condition when the systolic pressure well below 120. Similar to hypotension, orthostatic hypotension is the transient hypotension associated with feeling light-headed after standing up.

36) Formula for NFP (and its clinical significance) – in cardiology, the net filtration pressure is used to calculate the pressure exerted against the vessel wall, adjusting for the counter-pressure exerted by the osmotic pressure. A positive pressure on the arterial side indicates fluid is being pushed out of blood vessels and into the interstitial space and the lymphatic system. A negative pressure on the venous side indicates fluid is being absorbed from the interstitial fluid and returned to the systemic blood supply. The formula for calculating the net filtration pressure is:

NFP = (BHP + IFOP) – (IFHP + BOP)

Where, BHP = hydrostatic pressure of the blood BOP = osmotic pressure of the blood IFHP = hydrostatic pressure if the interstitial fluid IFOP = osmotic pressure of the interstitial fluid

37) Lymphatic Capillaries – are the smallest of the vessels in the lymphatic system. In relative size, these are on the order of vascular capillaries, but are blind-ended. Rather than connect two vessels, as vascular capillaries do with arterioles and venules, lymphatic vessels can be found throughout the interstitial space, collecting excess interstitial fluid. However, unlike vascular capillaries, lymphatic capillaries are not found in bone, teeth, bone marrow or the central nervous system. Additionally, lymphatic capillaries have two structural modifications unique to the lymphatic system – 1) the endothelial cells of the vessel walls are not tight, but more characteristic of very loose gap junctions – providing a high degree of porosity (and allowing interstitial fluid much easier entrance into the capillaries) – and the overlapping edges of adjacent cells create flow-restrictive valves (analogous to the valves seen in the vascular system), and 2) the collagenic fibers surrounding the capillaries – and serving as the structural matrix – are anchored to the valves in the capillaries, so that any increase in interstitial fluid volume – rather than force the capillaries to collapse – increases tension on the collagenic fibers, opening the network of valves – and adding to the structural integrity of the lymphatic capillaries. This has the overall effect of opening the valves when the hydrostatic pressure of the interstitial fluid is

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greater than the hydrostatic pressure inside the lymphatic capillaries (and keeping the capillaries from collapsing), and closing the valves when the hydrostatic pressure in the lymphatic capillaries is greater than the hydrostatic pressure – and preventing lymphatic fluid from escaping and flowing back into the interstitial spaces. Also in contrast to vascular capillaries, proteins are able to enter lymphatic capillaries. When surrounding tissues become inflamed, lymphatic vessels become very porous – allowing much larger particles (cellular debris, bacteria, virii, phages, oncogenic cells) to enter the lymphatic system. Any of these larger particles would pose a threat to both the vascular system as well as the body, but the lymphatic vasculature is routed through a network of lymph nodes throughout the body, and these lymph nodes – containing large numbers of macrophages and lymphocytes – act as filters to remove (or initiate an immune response) these larger particles from the lymph before they have a chance to enter the vascular system.

38) Sympathetic Effect on Blood Vessel Diameter – the tunica media of the vascular system is innervated by the sympathetic nervous system, and has the effect of vasoconstricting or vasodilating, respectively, the vessels on stimulation (or inhibition) by the sympathetic nerve fibers.

39) Hormones Affecting Blood Pressure – hormones affecting blood pressure are 1) epinephrine/norepinephrine 2) angiotensin II 3) ADH 4) ANP, and 5) histamine. Epinephrine/norepinephrine is an adrenergic hormone which stimulates vasoconstriction. Angiotensin II is part of the renin-angiotensin system. As renin is released by the kidneys in response to either a decrease in blood pressure or blood volume, it cleaves angiotensinogen – converting it to angiotensin I, which is converted to angiotensin II by angiotensin I-converting enzyme (ACE). As angiotensin II levels increase in the blood, it triggers systemic vasoconstriction to temporarily increase blood pressure (and the macula densa secretes prostaglandins to stimulate localized vasodilation, to prevent an increase in renal vascular pressure). Angiotensin II also triggers the adrenal glands to release aldosterone to increase Na+ resorption – and that triggers an accompanying resorption of H2O, which increases blood volume (having a concomitant effect on systemic blood pressure). Angiotensin II also stimulates the hypothalamus to release ADH to increase H2O retention – increasing blood volume in emergencies. ADH, secreted by the posterior lobe of the pituitary, is another hormone that works in coordination with angiotensin II. In this case, ADH is secreted in response to the body being severely dehydrated and needs to retain as much water – increasing blood volume and blood pressure – as possible. While epinephrine/norepinephrine, angiotensin II, and ADH all work to increase blood pressure, ANP (atrial natriuretic peptide) functions to inhibit the effects of these hormones - when the blood volume or blood pressure has increased and returned to normal values. ANP functions to prevent intravascular pressure from increasing too much and possibly rupturing a blood vessel, or retaining too much water and destabilizing the fluid balance between the ICF and ECF. Histamine is a vasodilator involved with inflammation/histamine/allergy reactions. In response to a foreign antigen, a histamine/allergic reaction often results and as part of the immune response eosinophils, basophils, and monocytes will often release histamine. As histamine is released, it acts as a vasodilator, allowing more cells to reach the site of infection – and as a result of its vasodilator effects, there's a decrease in blood pressure.

40) Lymph Characteristics (origin and development) – the lymphatic system is composed of an elaborate network of vessels very similar to the circulatory system. These vessels collect excess fluid that diffuses out of the bloodstream and into the interstitial fluid – once this fluid has left the bloodstream, it is called lymph. Like the circulatory system, the lymphatic system is one-way – but unlike the circulatory system, the lymphatic system begins with lymphatic capillaries (in contrast, the circulatory system begins with the great vessels and works its way down to the capillary beds and back up again to the great

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vessels). Lymphatic vessels fill the intercellular spaces, so are more diffuse and numerous than vessels in the circulatory system. As widespread as the network of lymphatic vessels is, they are not found in bone, teeth, bone marrow, or the central nervous system. The lymphatic system is essential for absorbing digested lipids and transporting triglycerides through the left thoracic trunk and into the left subclavian vein. Histologically, lymphatic vessels contain the same tissue layers (tunica intima, tunica media, and tunica externa) but the tissue layers are not as thick. Because the lymphatic system is a passive-pump system (it has no source to create positive pressure), lymph only moves through the vessels by compression of surrounding tissue. Because of this, the smaller lymphatic vessels parallel the body's superficial blood vessels (and use the body's musculature) to create the pressure it needs to move lymph through the vessels), and the larger vessels parallel the larger blood vessels (using pressure created by deep muscles and organ systems pressing against the skeletal system to generate the pressure it needs). Just as blood contains formed elements, lymph contains T cells, B cells, macrophages, dendritic cells, and reticular cells (which help support the collagenic matrix of the lymph nodes). Throughout the entire lymphatic system, a vessel will swell – forming a mass of loose, reticular connective tissue. These masses become encapsulated – developing distinct cortical and medullary regions, with several vessels leading in and out. These lobes develop into lymph nodes, which serve as the lymphatic system's filtration system – for removing all harmful or foreign material from the lymph. Once the lymph has been filtered, The T cells, macrophages, phagocytes, and B cells attack and destroy the material. Other than the lymph nodes, the spleen, thymus, and tonsils are lymphoid organs which serve the same purpose. After lymph has passed through the lymph nodes, it passes back into the interstitial fluid, and from there it diffuses back into the bloodstream – filtered and free of any bacteria or pathogens that may have been present.

41) Lymphatic System Functions – As blood flows throughout the body in the vascular system, nutrients, metabolic waste products, and dissolved gases in the plasma diffuse back and forth through the vessel walls. Substances entering the interstitial fluid must be able to diffuse back and forth – otherwise hypovolemic shock will be the result. Fluids and other substances which diffuse from the blood into the interstitial fluid often make their way back, but it is not always an even exchange – as there is always about 3 L/day of fluid and solutes that remain in the interstitial fluid. Once in the lymphatic system, lymph nodes found throughout the lymphatic system serve as a filter to remove all foreign or hazardous material from the interstitial fluid. As the lymph is filtered, cellular debris, bacteria, and other harmful particles are removed. The filtrate that's removed remains in the lymph nodes, and triggers lymphocytes, phagocytes, and macrophages to attack and destroy the particles – recycling them if they are cellular debris, or excreting what cannot be recycled. As lymph exits the lymph nodes, solutes diffuse back into the interstitial fluid - and from there, back into the bloodstream.

42) Non-Specific Body Defenses Against Infection – the human body has two branches of non-specific defenses against infection – an external and an internal branch. The external branch includes the skin and the mucus membranes. More specifically, the skin includes the keratinized epithelium, as well as skin secretions (sweat and sebaceous secretions) which make the skin acidic – inhibiting bacterial growth. At its simplest, mucous membranes make a very simple and effective barrier. In the respiratory and digestive tracts, mucus quickly traps microorganisms. Nasal hairs and respiratory cilia trap and filter microorganisms in the trachea and nose. Gastric juices in the stomach (containing concentrated HCl and proteases) quickly destroy any bacteria or pathogens. In females, the vaginal canal itself is very acidic – inhibiting bacterial growth. Lacrimal secretions and saliva continuously lubricate and clean the eyes and mouth – keeping any bacteria from growing. Even urine, with its normally acidic pH inhibits bacteria from growing – preventing urinary tract infections from developing. The internal branch

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includes phagocytes, macrophages, NK cells, granulocytes, and antimicrobial proteins. Phagocytes and macrophages are perhaps the most pervasive internal defense, as they are able to attack, digest, and destroy a wide array of pathogens and bacteria. NK cells, working together with phagocytic cells, granulocytes, and B cells are a very potent combination – as NK cells have the ability to identify foreign cells or pathogens that other cells may not, and then be able to destroy them. The body's inflammatory/histamine response, as ubiquitous as it is, is very effective in preventing the spread of pathogens and bacteria. Antimicrobial proteins (such as interferons and the body's complement protein) are capable of protecting cells from being infected before T or B cells can initiate an immune response, and the body's complement is effective at killing bacteria by lysing their membranes – similar to the way T cells can by secreting cytokines. The body can also secrete pyrogens, as part of a histamine reaction, to induce a fever – which is a very effective antimicrobial – since bacteria have difficulty surviving if their environment becomes too warm.

43) Thymus Gland (function) – is an endocrine gland found in the mediastinum of the thorax. The thymus is functional shortly after birth until about age 25. During this time, immature T cells produced in the bone marrow are transported to the thymus and allowed to develop. Once T cells have developed, but are still inactive, they are transported to the thymic cortex where they go through positive selection – a process in which CD4+/CD8+ T cells are exposed to ‘self’ antigens complexed with MHC molecules. Those cells that recognize, and bind, to the complex survive – those that do not are destroyed by macrophages, because those T cells that either do not recognize, or bind strongly enough, to the antigenic complex will not recognize ‘non-self’ antigens and be able to initiate an immune response. During positive selection, CD4+/CD8+ cells which bind to MHC Type II molecules will develop and differentiate into CD4+ cells, while CD4+/CD8+ which bind to MHC Type I molecules will develop and differentiate into CD8+ cells. During differentiation, a cell’s binding affinity determines whether the cell continues to develop – if a CD4+/CD8+ cell retains its binding affinity, it will downregulate its CD8 expression – becoming a CD4+ cell. Conversely, if the cell loses binding affinity, it will stop downregulating its CD8 expression, and start downregulating its CD4 expression – becoming a CD8+ cell. T cells which are selected through positive selection move deeper in the thymus, closer to the corticomedullary margin, and begin negative selection. In this phase, the surviving T cells are again presented with MHC-antigen complexes bound to native cells such as macrophages or dendritic cells (antigen-presenting cells – APC’s). In this phase, the selection is not testing for those that do/do not bind to the antigen – but rather those cells which bind too strongly to the MHC-antigen complex. This phase is important because those cells which bind too strongly are likely to trigger an immune response that develops into an autoimmune disease. As before, any cells that bind too strongly will be destroyed by macrophages. Those cells which survive both selection phases are now ready to be activated. Activation occurs by cells (dendritic cells, macrophages, or B cells) expressing non-self antigens being presented to the inactive (naïve) T cells – triggering the release of cytokines by the T cells. CD4+ cells release cytokines which signal macrophages, other phagocytic granulocytes, or B cells – as well as cell messenging cytokines which coordinate the cell’s interactivity with each other. CD8+ cells are able to function without releasing cytokines – actively moving through the blood stream, searching for non-self particles or pathogens, and initiating an immune response when they are found.

44) NK Cells – are a population of T cells which are CD16+CD3- and possess characteristics of both CD4+ and CD8+ cells – with one major difference. Where both CD4+ and CD8+ cells need to have antigen presented to them as part of an MHC-antigen complex, NK cells are able to initiate an immune response directly. NK cells are effective against some oncogenic cells as well as cells infected with either HSV-1 or HSV-2.

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45) T Cells – are the collective cell line of T lymphocytes which, after developing and differentiating in the thymus, are identified by one or more of the surface markers expressed on their cell membrane. The most common are the CD3+, CD4+, CD8+, and CD16+. T cells moderate the cell-mediated immune response, coordinating with B cells (which moderate the antibody-mediated immune response) – as a non-self antigen is detected, it activates the T cells, which release cytokines to stimulate the conversion of B cells into plasma cells, and stimulate the production of antibodies. In secondary immune responses, this process is often truncated – because memory T cells, which already have the antigenic epitope(s) from a previous immune response, are able to produce antibodies much faster and deal with a localized response rather than a prolonged, systemic, response.

46) Helper T Cells – are those T cells identified by expression of the CD4+ surface marker. CD4+ cells are one half of the CD4+/CD8+ model – where CD4+ cells identify non-self antigens and trigger an immune response by presenting them to macrophages for phagocytosis or B cells to trigger antibody production; and CD8+ cells do not require the release of messenger cytokines (as CD4+ cells do) in order to launch an immune response – being able to release cytotoxic cytokines (perforin, granulysin, and other proteases) directly into the cell – which destroy the cell membrane and cellular proteins. CD4+ cells are also targeted by the HIV-1 (HTLV-III) virus – using an RNA reverse transcriptase to convert the viral RNA into a complementary DNA sequence and insert it into the cell’s DNA. Once inserted, the viral DNA takes control of the cellular processes, to fabricate and construct new virions. When the cell reaches its viral load capacity, the cell membrane ruptures – releasing the new virions into the blood stream to repeat the process. In this manner, CD4+ cells are compromised and destroyed – leaving a decreasing number of CD4+ cells – and the body’s inability to fight off opportunistic diseases.

47) Antibody-mediated Immunity – is that branch of the immune system (and immune response moderated by B cells.

48) Cell-mediated Immunity – is that branch of the immune system (and immune response) that is moderated by T cells.

49) Genetic Recombination – is the immune system’s ability to randomly select and assemble genes in a multitude of different combinations – with the result being the body’s ability to create millions of different antibodies from the 25,000 genes each cell possesses to code for all the proteins it must synthesize.

50) Immunoglobulins (5 classes of Ig’s and respective functions) – are a class of molecule synthesized by plasma cells following exposure to an antigen. On introduction of an antigen into the body and exposure to it, B cells are converted to plasma cells – and it is these plasma cells which then begin producing immunoglobulins (antibodies) in response to the ‘non-self’ antigen that triggered the immune response in the B cells. Immunoglobulins are a class of proteins found in the blood, known as gamma globulin proteins. Structurally, immunoglobulins are composed, bilaterally, of a heavy chain (κ) linked to a light chain (λ) and look like the letter ‘Y’. The heavy chains contain a variable region and three constant regions, while the light chains contain a variable region and a single constant region. The variable regions of each chain are arranged opposite each other, creating the antigen-binding site of each arm. Between the first and second constant regions of the heavy chain are two S-S disulfide bonds, forming a hinge at the base – allowing a wide degree of conformational variation in the structure of the

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immunoglobulin molecule. Plasma cells are capable of producing five different classes (isotypes) of immunoglobulins – found in different parts of the body and with different functions.

a. Ig γ (Immunoglobulin G) Found in the standard monomer (κ2λ2) configuration Serum level = 80% Provides protection against bacteria, viruses, and toxins found in the blood and lymph Able to cross the placental barrier, providing passive immunity to the developing fetus People with type O blood form anti-A and anti-B antibodies that are IgG-based

b. Ig α (Immunoglobulin A) Found in a linear (κ4λ4) dimeric configuration Found in both serum and secretory forms

i. Serum isotype is produced by B cells in red bone marrowii. Secretory isotype is produced by mucosal B cells and secreted in colostrum,

maternal milk, tears, and saliva Serum level = 15% Gonorrhea (N. gonorrhœae) releases a protease which destroys IgA

c. Ig μ (Immunoglobulin M) Found predominately in a pentameric or hexameric (κ10λ10 or κ12λ12) ring configuration,

but can exist in the standard monomer (κ2λ2) configuration Serum level = 5% In its monomeric form, it is attached to B cells and serves as an antigen receptor In its pentameric/hexameric form it is the first class of antibodies released as part of an

immune response Its multiple binding sites make IgM a very strong antibody IgM does not cross the placenta Elevated serum IgM levels are often indicative of current or prior infection People who have type A/B/AB form anti-A and anti-B antibodies that are IgM-based

d. Ig ε (Immunoglobulin E) Found in the standard monomer (κ2λ2) configuration Serum level = <1% Slightly larger than IgG Secreted by plasma cells in the skin, mucosae of the gastrointestinal and respiratory

tracts, and the tonsils In inflammation reactions, IgE’s stem binds to mast cells and basophils – and when

antigens bind to its antigen-binding sites, IgE triggers the cell to release histamine (or other anti-inflammatory compounds) to counter inflammation or a hypersensitivity reaction

Normally, serum IgE levels are very low – but rise in response to hypersensitivity reactions or chronic parasitic infections of the digestive tract

e. Ig δ (Immunoglobulin D) Found in the standard monomer (κ2λ2) configuration Serum level = <1% In the 46 years since its discovery, very little is still known about IgD and its function

within the body Almost always found attached to plasma cells, as an antigen receptor (like IgM in its

monomeric form

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IgD has recently been found to bind to basophils and mast cells (in the same manner as IgE) to produce antimicrobial factors that take part in defending against respiratory infections

51) Antibody Titer – is the lowest serial dilution (1:1, 1:2, 1:4, 1:8, 1:16, etc) which still gives a positive result for the antibody, antigen, or surface marker being tested. Titer levels are most useful in determining the lowest concentration of a virus or other infectious agent that is still capable of infecting a host cell. Titer is also used to categorize fats – the titer being the temperature (◦C) at which the fat solidifies, as well as categorizing the fat as a tallow (titer is ≥ 40°C) or a grease (titer is ≤ 40°C). As important as antibody or antigen titers are, phage titers are even more important. Phage titers are used in constructing genetic libraries of phage genomes, and the titers are used to ensure there are enough phage particles to represent the entire genome of the phage.

52) Autoimmunity – occurs at some point in an individual’s life when their immune system stops identifying systemic structures as ‘self’, and starts identifying it as ‘non-self’ and mounts an immune response against it. The latest research has not been able to identify specific causes as much as determining factors. These factors can be broken down into 1) genetic predisposition 2) gender predisposition, and 3) environmental factors.

Genetic predisposition involves congenital or point mutations in genes coding for the body’s immunoglobulins, T-cell receptors, or the body’s MHC Type I/II allotypic molecules. Any number of point mutations to the genes coding for the body’s immunoglobulins or T-cell receptors could result in a variety of autoimmune diseases of varying severities. Point mutations to any of the body’s MHC molecules are, for the most part, ‘self-correcting’ – in that any molecules that the body detects as ‘wrong’ are broken down, recycled, and replaced with ‘correct’ molecules. Some of these molecules however, even though they have the correct primary and secondary structures, and appear ‘correct – may, in fact, have errors in their tertiary (or even quaternary) structures that are not detected – and play a role in autoimmune diseases with no association to mutations in either immunoglobulins or T-cell receptors (specifically – the human leukocyte antigen (HLA)-DR2 is associated with SLE (systemic lupus erythematosus), narcolepsy, and multiple sclerosis (MS), HLA-DR3 is associated with Sjögren's syndrome (it attacks the body’s exocrine glands), myasthenia gravis (MG), SLE, and type I diabetes, and HLA-DR4 is associated with the onset of rheumatoid arthritis (RA), and type I diabetes). Although associations between MHC Type II molecules and autoimmune diseases have been presumed, the only association (and yet-to-be verified) is HLA-B27 and ankylosing spondylitis (a variant of rheumatoid arthritis, that affects the lower intervertebral joints and the sacroilium of the pelvic girdle – in its worst form, it can result in the fusion of the entire spine).

Gender predisposition, from the latest research, indicates a tentative association between autoimmune diseases and mutations on the X chromosome – making these X-linked autoimmune diseases. Although nearly 75% of patients are female, these diseases are not restricted to females – and it is being found that these X-linked autoimmune diseases present themselves more severely in males than in females. Some of these X-linked diseases include ankylosing spondylitis, type I diabetes, psoriasis, and Crohn’s disease (an autoimmune disease of the gastrointestinal tract causing inflammation of the tissue).

Environmental factors, while tenuous, do show a clear association between autoimmune diseases and the environment. Of interest is the inverse correlation that appears to exist between infectious diseases and the incidence of autoimmune diseases. Studies have shown that in areas where infectious diseases are endemic, the incidence of autoimmune diseases is very low – if at all. The proposed infection model is that the infectious disease so attenuates the body’s own immune system, that infection

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with the disease not only prevents the body from mounting an immune response against the disease, but suppresses the body’s autoimmune response – causing an observable, if not temporary, palliative treatment for the autoimmune disease. This is proven by leaving the geographical area and treating for the infectious disease – once the patient has been treated for the disease, the body’s immune system, no longer feeling the attenuation effects of the disease, returns to identifying its cells and tissues as ‘non-self’ and attacking them. This can perhaps best be illustrated by inducing the onset of lupus erythematosus in a patient by the administration of drugs or other chemical agents (in a controlled setting). Without any predisposition or other contributing factors, a disease like lupus erythematosus (LE), can be induced by the administration of drugs or other chemical agents – and once they have cleared the patient’s system, the symptoms of the disease also disappear.

53) Retrovirus – is a class of virii which encodes its genetic material as RNA, rather than DNA (as in most virii), and its infection vector is very similar to that of a parasite. Once it infects a host cell, the RNA is encoded as DNA by means of an RNA reverse transcriptase. Once the host cell has been infected, and the virus’ RNA has been translated into DNA (and inserted into the DNA of the host cell), the retrovirus is now known as a provirus (a virus that doesn’t duplicate its own DNA, but inserts its DNA into the host DNA – taking control of the host’s biochemical pathways and using them to replicate the virus in large quantities, until the host cell has reached the end of its lifespan). At this time, the virus causes the host cell to rupture, releasing millions of new copies of the virus – to infect more host cells.

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